The invention relates to a pharmaceutical formulation in the form of instant granules according to the precharacterizing clause of claim 1. Such a formulation is described, for example, in EP-B1-232,277. Said publication discusses the fact that, according to the invention, an amino acid (e.g. tryptophane in Example 1) can be processed as an active substance or a plurality of active substances (e.g. vitamins and mineral salts in Example 2, applied to a carrier material comprising acid, which presents a problem for kidney patients) can be processed, it also being stated that a plurality of layers can be applied to the granular carrier material of soluble carbohydrate by means of a binder solution, for anchoring relatively large amounts of active substance.
This last proposal is subject to limits in practice, especially in the case of amino acids, unless special measures are taken. In particular, it has been found that, for amounts of active substance which are greater than the amounts occurring in the examples mentioned in EP-B1-232,277 and for active substances which are very bulky, the active substances on the carbohydrate carriers cannot be sufficiently anchored by the binder layer alone and too much active substance remains free, with the result that neither the desired suspension property nor the flowability of the product can be satisfactorily achieved.
In the case of amounts of active substance of from 60 to 100 parts by weightxe2x80x94based on 100 parts by weight of carrierxe2x80x94undesired agglomerations of the active substance occur when the binder is applied repeatedly, so that, on introduction into water, the desired suspension is no longer achievable and the particles sink to the bottom or remain on the surface of the water.
It is therefore one object of the invention to improve the formulation described in EP-B1-232,277 and its preparation in such a way that instant granules and a process for their preparation are provided, by means of which it is possible easily to accommodate even very large amounts of even differentxe2x80x94in particular insoluble or slightly solublexe2x80x94active substances, in particular a plurality of amino acids, analgesics, antioxidants, such as, for example, paracetamol, beta-carotene, etc, After introduction into water, the pharmaceutical formulation should be suspended within an appropriately short time by stirring, should have a pleasant taste and should furthermore remain in suspension for an appropriately long time.
This requirement is particularly applicable to amino acids because they have to be administered in large amounts per dose, both when used as a food supplement and particularly as a preparation for kidney patients who have to survive on a low protein diet and require a large supply of amino acids. By supplying essential amino acids, the deficit can be satisfactorily compensated, with the result that adverse symptoms can be prevented and the necessity of a dialysis can in certain circumstances be postponed.
There are on the market a number of amino acid-containing products with essential amino acids in tablet or capsule form, but, for example, kidney patients have to take 5 units of these, 3 times a day, which presents considerable problems for the patient or consumer, all the more so since this group ofxe2x80x94mostly elderlyxe2x80x94patients usually also has to take a number of other medicaments, generally in tablet form. A dosage form which can be administered in liquid form in order to facilitate the intake for the patient was therefore desirable for this amino acid medication.
A further object of the invention was therefore to develop an instant formulation comprising a high dose of active substance and small amounts of excipients, which formulation can be readily suspended in a small amount of water, say from 50 to 100 ml, and is readily accepted by the patient with regard to taste. Consequently, consumption by the patient should be substantially facilitated.
The difficulty of developing such a product which is suspendable in water was associated with the weight ratios and volume ratios of carrier material to active substance. Granulation of the active substances alone did not achieve the object since this resulted, on the one hand, in agglomerates of the active substances which did not disintegrate into their individual particles within the distribution time in water, therefore were insufficiently suspendable and sank to the bottom of the glass, on the other hand the active substance partially did not granulate at all and was therefore floating to the surface and no proper suspension could be achieved (see negative Example 1).
A similar, slightly better, effect occurred when excipients were granulated together with the active substances, since in this case, on the one hand, the addition of solution caused the easily soluble carrier materials to agglomerate and, in another case, the resulting granulation of the particles of active substance was insufficient for achieving a flowable product (see also negative example 2).
The application of a phospholipid (Epikuron(copyright)) solution as a surfactant to the granulated active substances well as to excipients granulated together improved the suspension of the active substances, but coarser particles still remained in the suspension and a part of the active compound was still floating to the surface (see negative examples 1a and 2a).
When a corresponding amount of binder was added to the solution, the result was an undesired coarse-particle agglomeration of the active substances and/or of the active substances with the carrier material, which, in spite of milling to the desired particle size, exhibited reduced suspension properties and settled on the bottom when stirred into water.
All these problems have been overcome according to the invention by anchoring only a part of the active substances on a first, preferably compact and/or crystalline, carrier material having a bulk density of between 58 and 100, preferably between 60 and 95 g/100 ml, while the excess of the active substances not anchored to the surface of the first carrier material is granulated by means of the introduction of a second, voluminous, e.g. spray dried, carrier material which is selected from carrier materials having a bulk density of between 30 to 55, preferably between 33 and 50 g/100 ml and thereby are usually more easily and/or quickly soluble than the first carrier material. Preferred carrier materials are listed in Table 1.
The bulk density of conventional products available on the market is not directly depending on the grain size distribution which may widely differ.
Advantageous embodiments, further developments and improvements of the invention are described in the dependent claims.
This invention was based on the consideration that, in cases where small amounts of excipients are desired, either on the basis of dietary or medical indication or for economic reasons, it is necessary to find a procedure which makes it possible to combine bulky insoluble or slightly soluble active substances in a weight ratio of from 60 to 100 parts by weightxe2x80x94with 100 parts by weight of the total carrier material.
This is possible by introducing the carriers in two or more stages. In the first step, a part of the total carrier materialsxe2x80x94consisting of at least 80, preferably at least 100% by weight of the first carrier materialxe2x80x94is initially taken; the surface is then wet by adding water, ethanol, an ethanol/water mixture and/or a binder solution. Thereafter, the active substances are added and are at least partly anchored to the surface of the carrier particles. In a second step, by introducing a further carrier material and by partially dissolving its surface by means of the residual moisture present in the materialxe2x80x94or if required with the addition of further water, ethanol, an ethanol/water mixture or a binder solutionxe2x80x94the remaining, still unanchored particles of active substance are, at least partially, anchored thereon and/or are granulated with the second carrier material. This step canxe2x80x94if requiredxe2x80x94be repeated.
In practice, it has been found that the best results are obtained with an amount of liquid of from 1 to 10, preferably of about 3 to about 7 parts by weight (based on 100 parts by weight of carrier material and active substance). The lower limit is applicable when using pure water and substantially insoluble or very slightly soluble active substances; an average value is to be assumed in the case of ethanol or ethanol/water mixtures and also sparingly soluble active substances; the upper limit is applicable when a binder solution is used, especially if the carrier particles and the active substances are less susceptible to agglomeration.
It has furthermore proved expedient if initially only from 10 to 25, in particular from 15 to 20, % by weight of the intended total amount of liquid are used for wetting the first carrier material. This should in fact be essentially moistened but only minimally superficially dissolved since otherwise the carrier material has the tendency to agglomerate itself, with the result that uniform distribution, namely uniform application of the active substance to the individual carrier crystals, becomes more difficult.
The remaining amount of liquid is then used for wetting the remaining active substance and the second carrier material. In many cases, it has proved expedient for the same reason, namely for the avoidance of agglomeration of the carrier material, to distribute the remaining amount of liquid over the first carrier material already covered with particles of active substance and over the free particles of active substance before the addition of the second carrier material. Depending on the type of ingredients and on the procedure, articles of the second carrier material coated analogously with active substance and/or particles granulated with active substance and carrier material are then obtained.
It is then possible to proceed as follows for a formulation in which free-flowing, suspendable granules are to be obtained from 70 to 80 parts by weight of bulky, insoluble or slightly soluble active substances on 100 parts b weight of carrier:
In the first step, from 60 to 80% of particles of the first carrier material are wet with, for example, a binder solution. The binder solution may be an ethanolic or an ethanol/water solution of at least one of the following substances: sugar, sugar alcohol, maltodextrin, polyvinylpyrrolidon or other hydrocolloids. In some cases it is preferable to slightly wet the particles of the first carrier material with ethanol or with an ethanol/water-mixture 70:30 before applying the binder solution in order to avoid an undesired agglomeration of said particles.
Thereafter, at least a partxe2x80x94preferably the major partxe2x80x94of the active substances is added and at least partially anchored on the surface of the carrier particles. Optionally, the remainder ofxe2x80x94or some additionalxe2x80x94liquid is added, and the remaining particles of active substance are wet by means of said additional binder solution and fixed to the existing particles of the first carrier materialxe2x80x94which are already covered by a part of the active substancexe2x80x94and/or to one another. In case the surface of the first carrier material and/or of the active substances is too much dissolved, it might be advantageous to partially dry the mixture before or during the addition of the remaining part of said liquid, of particles of the second carrier material, and/or of any remaining part of the active substances.
This is followed, in a second step, by the addition of the second carrier material. For example spray-dried, spray granulated or agglomerated materials, for example sugar alcohols, such as sorbitol, xylitol or mannitol; instant sugar (i.e. spray dried saccharose), and further hydrolyzed starch products such as maltodextrin, soluble corn syrup solids or starch sugar (e.g. dried glucose syrup), are suitable for this purpose owing to their bulk density, the fluffy, bulky structure an the good surface dissolution capability. If maltodextrin is used as a second carrier material, a particle size distribution of 20-25% greater than 0.4 mm, 35-65% less than 0.4 mm greater than 0.1 mm and a maximum fraction of 20-35% less than 0.1 mm is advisable. Naturally the above specified second carrier materials may also be supplied by other processes, besides spray drying and spray granulating, provided that the carrier materials are obtained within the appropriate bulk density.
Because of the moisture already present in the material or, if required, optionally an additionally introduced one, the surface of the second carrier particles now also partially dissolves and the still free active substances are anchored thereon; on the other hand, the second carrier particles serve as a core for granulation of the still not anchored active substances, with the advantage that, upon the introduction to water, the core quickly dissolves, the particles of active substance are released and hence a good suspension is permitted. The carrier materials can also be introduced in a plurality of steps. Would the second carrier material be introduced at an earlier stagexe2x80x94when there are no amino acids acting as a buffer yetxe2x80x94agglomeration of the carrier particles would occur before the active substances could be anchored on the carrier particles"" surface.
Compact, for example, sorbitol or mannitol can be used as the first carrier material. In the case of such sugar alcohols, an excessively large dust fraction should be avoided in order to prevent agglomeration of the carriers on moistening by partial dissolution of the fine fractions; preferably, a maximum of only 5% of the carrier particles are smaller than 0.1 m. They may be present both in crystalline form and as spray-dried or granulated raw material. Furthermore, sucrose having the following particle size distribution may also be used as carrier material:
 less than 0.5 mm greater than 0.3 mm: 0-60% by weight
 less than 0.3 mm greater than 0.1 mm: 10-85% (the main sieve fraction)
 less than 0.1 mm: 0-15%
For amino acids following particle size distributions may be applicable: In the group of L-isoleucine, L-leucine and L-valine, a maximum of 15% by weight should be  greater than 0.3 mm, 70-95% by weight should be between 0.1 and 0.3 mm, and 1-20% by weight should be  less than 0.1 mm. In the group of L-phenylalanine, L-histidine, L-methionine, L-threonine, L-tryptophane and L-tyrosine, a maximum of 5% by weight should be  greater than 0.3 mm, 30-90% by weight should be between 0.1 and 0.3 mm, and 5-60% by weight should be  less than 0.1 mm. In L-lysinacetate, 5-30% by weight should be  greater than 0.3 mm, 30-70% by weight should be between 0.1 and 0.3 mm, and a maximum of 25% by weight should be  less than 0.1 mm.
For xcex2-carotene or DL-xcex1-tocopherolacetate, a maximum of 15% by weight should be  greater than 0.3 mm, 70 to 95% by weight of the particle size distribution should be between 0.1 and 0.3 mm, and a maximum of 30% by weight should be  less than 0.1 mm.
To achieve an improvement in the suspension, taste improving and/or suspension aids, such as Ca(H2PO4)2.H2O or trisodiumcitrate.2H2O. Both and other soluble alkaline salts of edible organic acids can also act as carrier materials. For instance, trisodiumcitrate.2H2O together with further carrier materials my be used as first carrier. Wetting agents may also be used, too. Both anionic surfactants, such as sodium laurylsulphate or dioctyl sulphosuccinate, and sugar esters, phospholipids, polysorbates or hydrogenated castor oils are suitable for this purpose.
For improving the taste, artificial sweeteners and flavors, or acids or their acidic salts, in the allowed amount or amount permitted for the patient group, and also vitamins may be added to the formulation.
It is thus possible, according to the invention, to combine vitaminsxe2x80x94such as ascorbic acid, B-vitamins, folic acid, biotin, calcium pantothenate, as well as fat soluble ones such as tocopherol, retinol and cholecalciferol (vitamins A, D and E)xe2x80x94and also, if required, trace elements such as selenium, chromium, manganese, molybdenum, zinc, iron and minerals such as magnesium and calciumxe2x80x94with the active substance, for example amino acids.
Accordingly, it is also possible to apply at least one antioxidant and/or vitamin as the active substance together with trace elements such as selenium, chromium, manganese, molybdenum, zinc, iron and/or minerals such as magnesium and calcium.
A particular formulation is an amino acid instant formulation for kidney patients. For medical reasons, special attention must be paid to the composition of the formulation in this case. For example, a dose which is administered three times a day should contain as little sugar as possible, and mannitol or sorbitol in an amount of not more than 1.5 g, and furthermore as small an amount as is possible of organic acids, such as citric acid or tartaric acid or their acidic salts. Phosphate-containing excipients are also undesirable.
The essential amino acids, i.e. L-valine, L-isoleucine, L-tyrosine, L-threonine, L-methionine, L-leucine and L-lysine, should be present in a corresponding amount per dose, the addition of some further amino acids being expedient, such as, in particular, L-histidine, L-tryptophane, L-phenylalanine and arginine aspartate. If the daily requirement is distributed over three doses, for example, 450 mg of L-leucine, 675 mg of L-valine, 300 mg of L-isoleucine, 325 mg of L-histidine, 375 mg of L-tyrosine, 125 mg of L-tryptophane, 325 mg of L-threonine, 40 mg of L-methionine, 350 mg of L-phenylalanine and 480 mg of L-lysine acetate per dose have proved expedient.
Instant granules according to the invention and containing said doses can be readily suspended in 50 to 100 ml of water andxe2x80x94together with sweeteners and flavorsxe2x80x94are pleasant to drink. Since kidney patients are limited in their liquid intake, it was necessary to solve the problem of developing an instant product which has sufficiently good suspension properties in a very small amount of solution, it being necessary for the amount of water per dose as far as possible not to exceed 100 ml. The product can also be suspended in 50 ml of water but the stability of the suspension is better with a larger amount of water, so that dissolution in 75 ml of water is recommended.
To check the stability of the suspension as a function of the amount of water, experiments were carried out to determine how much of the amino acids settle out per unit time. One pouch each of the product according to example 1 below was introduced into 50 ml, 75 ml and 100 ml resp. of water, stirring was carried out for 20 sec and the sediment was measured after 1 to 15 min. The vessel used was a 100 ml measuring cylinder having a diameter of 25 mm. The results are given in the following Table 2:
It was found that the suspension is very stable and only small differences were observed in an amount of 50 ml and 75 ml of water. The product exhibited slightly better behavior on dissolution in 100 ml of water. If the product is stirred into 50 ml and 100 ml of water in a glass, a slight sediment forms after one minute and no longer increases measurably after 20 to 25 minutes, and only the suspension becomes very slightly flaky.
These advantagesxe2x80x94from a technical point of view and in terms of tastexe2x80x94could only be achieved by means of the formulation and by the process for its preparation according to the invention based on the consideration that it is necessary to proceed in two stagesxe2x80x94on the one hand owing to the preferred, large amounts of active substance(s) and, on the other hand, also because of any use of carrier materials which are in fact particularly easily and rapidly soluble, such as, for example, spray dried or spray granulated sorbitol, xylitol, mannitol, maltodextrin, instant sugar and glucose syrup. Under certain circumstances, it may then even be expedient in any case to use the second binder solution based on ethanol or at best on an ethanol/water mixture, if further amounts of active substance are to be applied.
It was necessary to choose the composition and the process in such a way that agglomeration of the carrier substances could be prevented, in order to provide as large a surface as possible for the application of the active substances and, on the other hand, to wet and to partially dissolve the surface so well that a large part of the amino acids could be applied to the carrier surface. This could be achieved by the choice of the ingredients and by a composition according to the invention.
Furthermore, the acid componentsxe2x80x94in the formulation which contains sucrosexe2x80x94were not mixed with the carrier substances and wet, in order to prevent inversion of the sugar and hence undesired sticking together of the carrier materials due to the increased adhesiveness of the invert sugar. Consequently, the acidic components and the soluble lysine acetate were not added until shortly before the final drying, when only little moisture and adhesiveness of the granules were present, with the result that it was also possible to obtain a more stable product.